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Glucagon-Like-Peptide-1 Secretion from Canine L-Cells Is Increased by Glucose-Dependent-Insulinotropic Peptide but Unaffected by Glucose

Diabetes Discovery (A.B.D., H.K.), Novo Nordisk A/S, Novo allé, Dk-2880 Bagsvaerd, Denmark; and Department of Physiology (A.M.J.B.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Address all correspondence and requests for reprints to: Dr. Hans Kofod Diabetes Discovery, Novo Nordisk A/S, Novo allé, 6B3.99, Dk-2880 Bagsvaerd, Denmark. E-mail: HKO{at}novo.dk

Glucagon-like peptide-1(7–36)amide (GLP-1) is a potent insulinotropic peptide released from the small intestine. To investigate the regulation of GLP-1 secretion, we established a GLP-1 release assay based on primary canine intestinal L-cells. The ileal mucosa was digested with collagenase/EDTA to a single cell suspension and enriched for L-cells by counterstream centrifugal elutriation. We performed release assays on the cultured cells after 36 h, and GLP-1 in the supernatant was determined by enzyme-linked immunoabsorbent assay (ELISA).

Glucose-dependent insulinotropic peptide (GIP) dose dependently stimulated the release of GLP-1 and resulted in a 2-fold increase at 100 nM GIP. This effect was fully inhibited by 10 nM somatostatin. However, neither basal or GIP stimulated GLP-1 secretion were affected by ambient glucose concentrations from 5–25 mM. The receptor-independent secretagogues ß phorbol myristate acetate and forskolin dose dependently increased the secretion of GLP-1; effects inhibited by staurosporine and H8 respectively. Costimulation with GIP and phorbol ester, but not forskolin, resulted in an additive response. Furthermore, the effect of GIP could be inhibited by H8 but not by staurosporine.

These results indicate that glucose does not directly stimulate canine L-cells. It is more probable that glucose releases GIP from the upper intestine that in turn stimulates GLP-1 secretion. The ability of GIP to stimulate GLP-1 secretion is probably mediated through activation of protein kinase A.

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